Indirect Actions of Neurotransmitters

The ligand-gated ion channels provide a direct linkage between neurotransmitter binding and the change in postsynaptic ion permeability. The binding site for neurotransmitter molecules is part of the ion channel protein. In addition, however, postsynaptic effects of neurotransmitters often involve an indirect linkage, in which neurotransmitter binding and the change in ion permeability are carried out by distinct protein molecules. Separation of neurotransmitter binding and the postsynaptic response allows a single neurotransmitter substance to have diverse effects on a postsynaptic neuron closing one type ofion channel while opening others, affecting the metabolism of the postsynaptic cell as well as its membrane permeability, or altering gene expression.

The basic scheme for indirect actions of neurotransmitters is shown in Figure 9-12. Neurotransmitter molecules bind to a postsynaptic receptor molecule, as with ligand-gated ion channels. The receptor molecule is not itself an ion channel. Instead, the activated receptor molecule stimulates or inhibits production of an internal substance, called a second messenger (the neurotransmitter

1. Neurotransmitter is released by presynaptic neuron

2. Neurotransmitter combines with specific receptor in membrane of postsynaptic neuron

3. Combination of neurotransmitter with receptor leads to intracellular release or production of a second messenger

4. Second messenger interacts (directly or indirectly) with ion channel, causing it to open or close

Figure 9-12 Overview of the indirect linkage of a neurotransmitter to activity of an ion channel via an intracellular second messenger in the postsynaptic cell.

being the first messenger), that alters the state of the postsynaptic cell. Common second messenger molecules include:

• Cyclic AMP (cyclic adenosine monophosphate), which is produced from ATP by the enzyme adenylyl cyclase.

• Cyclic GMP (cyclic guanosine monophosphate), which is produced from GTP (the guanine nucleotide equivalent of ATP) by the enzyme guanylyl cyclase.

• The dual second messengers diacylglycerol and inositol trisphosphate, both of which are produced from a particular kind of membrane lipid molecule by the enzyme phospholipase C.

• Arachidonic acid, which is produced from membrane lipid molecules by the enzyme phospholipase A.

Second messenger substances have a variety of effects in postsynaptic cells. Excitation results if the second messenger promotes opening of sodium channels or closing of potassium channels. Conversely, if the second messenger results in opening of potassium or chloride channels, or closing of sodium channels, then inhibition results.

How are the second messenger and the target ion channel linked? In some cases, the second messenger molecule directly binds to the ion channel, causing it to open or close. For example, in photoreceptor cells of the retina cyclic GMP directly opens sodium channels in the plasma membrane. In other instances, the second messenger acts indirectly, by activating an enzyme that then affects the ion channel. For example, cyclic AMP activates an enzyme called cyclic-AMP-dependent protein kinase (or protein kinase A). Protein kinase A phos-phorylates proteins, by attaching inorganic phosphate to specific amino acids in the protein. Phosphorylation is a common biochemical mechanism by which protein function is altered, including ion channels. For example, phosphoryla-tion of voltage-activated calcium channels is necessary for normal operation of the channel. Thus, a neurotransmitter might indirectly affect calcium channels in a postsynaptic cell by altering the level of cyclic AMP and hence altering phosphorylation of the channels.

How is the activated neurotransmitter receptor molecule linked to enzymes that alter second messenger levels? Once again, the linkage is indirect and involves a protein called a GTP-binding protein (or G-protein). In its inactive state, GDP is bound to the G-protein. The neurotransmitter receptor molecule catalyzes the replacement of GDP by GTP on the G-protein and thus activates the G-protein. The activated G-protein then stimulates the enzyme that produces the second messenger (adenylyl cyclase in the case of cyclic AMP, for example).

Numerous varieties of G-proteins have been identified, each with specific effects on specific target enzymes. Some G-proteins stimulate the activity of the target enzyme, while others inhibit it. Thus, activation of one type of neuro-transmitter receptor molecule might increase the level of a second messenger, whereas activation of a different receptor molecule might decrease the level of the second messenger, depending on the type ofG-protein to which the receptor is coupled. In addition to acting via second messengers, activated G-proteins may sometimes serve as a messenger that directly activates ion channels.

The indirect actions of neurotransmitters are summarized in Figure 9-13. This sequence can be envisioned as an enzymatic cascade, in which an

Figure 9-13 The sequence of events in the indirect action of a neurotransmitter on membrane permeability of a postsynaptic cell. Ion channel activity may be altered by G-proteins, by second messengers, or by second-messenger-dependent enzymes. (Animation available at www.blackwellscience.com)

1. Neurotransmitter is released by presynaptic neuron

2. Neurotransmitter combines with specific receptor in membrane of postsynaptic neuron

3. Activated receptor activates G-protein

4a. Activated G-protein acts on enzyme that produces second messenger (e.g., adenylyl cyclase)

4b. Activated G-protein directly combines with and activates ion channel

5. Level of second messenger increases (excitatory G-protein) or decreases (inhibitory G-protein) in postsynaptic cell

6a. Second messenger activates an enzyme (e.g., protein kinase A)

6b. Second messenger directly acts on ion channel

7. Activated enzyme acts on ion channel to alter its function (opens channel, closes channel, or makes channel capable of responding to a stimulus, such as depolarization)

activated neurotransmitter receptor acts as an enzyme to activate G-protein, which in turn activates an enzyme that produces a second messenger. The second messenger then activates another enzyme that affects ion channel operation. In this sequence, an ion channel might be affected at three different points:

• Activated G-protein might bind to and activate an ion channel.

• The second messenger might directly bind to the channel.

• An enzyme, such as a protein kinase, that depends on the presence of the second messenger might act on the ion channel.

In all cases, the net excitatory or inhibitory effect of the neurotransmitter depends on the type of ion channel affected in the postsynaptic membrane and on whether the ion channel is opened or closed by the indirect action of the neurotransmitter.

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